Daily Archives: October 19, 2014

PUBLIC RELEASE DATE:

18-Oct-2014

Contact: Nalini Padmanabhan press@ashg.org 301-634-7346 American Society of Human Genetics @GeneticsSociety

BETHESDA, MD Human geneticists have discovered that a region of the genome associated with autism contains genetic variation that evolved in the last 250,000 years, after the divergence of humans from ancient hominids, and likely plays an important role in disease. Their findings were presented today at the American Society of Human Genetics (ASHG) 2014 Annual Meeting in San Diego.

Researchers at the University of Washington analyzed the genomes of 2,551 humans, 86 apes, one Neanderthal, and one Denisovan. They closely examined a region of human chromosome 16 known as 16p11.2, a region prone to genetic changes in which segments of DNA are deleted or duplicated, one of the most common genetic causes of autism, schizophrenia, and other conditions. The geneticists found that certain segments of DNA in this region are repeated a variable number of times in different people and may also be associated with disease.

To trace the origins of this variation, the researchers collaborated with colleagues at the University of Lausanne and the University of Bari to sequence and analyze corresponding regions of ape genomes.

"When we compared the genomes of apes and humans, we found that the humans had evolved complex structural changes at 16p11.2 associated with deletions and duplications that often result in autism. The findings suggest that these changes emerged relatively recently and are unique to humans," explained study author Xander Nuttle, BS, BSE, a graduate student in the Department of Genome Sciences at the University of Washington School of Medicine.

While this genetic variation has likely made humans more vulnerable to disease, the scientists believe it also contributed to the formation of novel genes. One such gene is BOLA2, a gene thought to be important in cell reproduction. The researchers found that while apes, Neanderthals, and Denisovans had only two copies of BOLA2, all modern humans have between three and 14 copies, with an average of six. The team is currently studying the function of BOLA2 to understand the potential significance of additional copies for human evolution.

"Another question we are exploring is why people with the same duplications and deletions at 16p11.2 vary in disease severity," Mr. Nuttle said. "Some people are healthy or have mild illness, while others are severely affected and have multiple clinical diagnoses."

One hypothesis is that differences among people in how the region is organized, such as the number of copies of genes like BOLA2 present and the precise locations at which deletions and duplications start and end, contribute to this variability. To examine this possibility, Mr. Nuttle and colleagues are analyzing DNA and medical data from over 125 individuals with deletions or duplications at 16p11.2.

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Gene duplications associated with autism evolved recently in human history

PUBLIC RELEASE DATE:

19-Oct-2014

Contact: Nalini Padmanabhan press@ashg.org 301-634-7346 American Society of Human Genetics @GeneticsSociety

BETHESDA, MD Breaking down complex conditions such as Type 2 Diabetes and obesity into the specific metabolic proteins and processes that underlie them offers a new approach to studying the genetics of these diseases and how they are interrelated, according to research presented today at the American Society of Human Genetics (ASHG) 2014 Annual Meeting in San Diego.

By studying specific proteins that contribute to such conditions and the genes that encode them scientists can develop new drugs that directly target the metabolic processes that do not function properly, explained lead author Jennifer E. Below, PhD, of The University of Texas Health Science Center at Houston (UTHealth) School of Public Health.

"In fact, genes that affect the same process at the protein level can end up influencing multiple traits in tandem," said Dr. Below. Working with colleagues at the Baylor College of Medicine, Harvard Medical School, and the University of Chicago, Dr. Below found that genes that regulate a person's circadian cycle affect quality of sleep but could also put him or her at risk for diabetes. Similarly, the researchers learned, a group of related proteins involved in immune system functions and interactions between cells also plays a role in heart health.

"Findings such as this highlight the importance of capturing the array of effects of genes, rather than treating each analysis as independent. Traits don't exist in silos; they are richly connected and interacting, and we benefit by acknowledging this in our genetic analyses," Dr. Below said.

The researchers have focused their efforts in Starr County, Texas, a community where trends in obesity and Type 2 Diabetes rates have steadily remained about 30 years ahead of the rest of the country. They have sequenced the genomes of more than 1,400 people in Starr County, studying relationships among many traits that affect obesity and diabetes, such as weight, sleep patterns, heart health, eye health, immune function, fat levels, and blood pressure. This allows them to tease apart the roles of lifestyle and environmental factors, including how these traits may affect one another.

"Rates of obesity and diabetes have been increasing at an alarming pace in recent decades," Dr. Below said. "While we know that the genes present in Starr County haven't changed over that period, genetics still presents the best opportunity to study what's happening. By breaking these conditions down into detailed traits and genetic sequence data, we could inform potential treatments," she explained.

In the future, Dr. Below and colleagues plan to study families in order to analyze rare genetic variants that may be present in larger numbers than in the general population, some of which may have a major effect on disease.

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Metabolic genetics research paves way to treating diabetes and obesity

PUBLIC RELEASE DATE:

19-Oct-2014

Contact: Nalini Padmanabhan press@ashg.org 301-634-7346 American Society of Human Genetics @GeneticsSociety

BETHESDA, MD A child's genetic makeup may contribute to his or her mother's risk of rheumatoid arthritis, possibly explaining why women are at higher risk of developing the disease than men. This research will be presented Tuesday, October 21, at the American Society of Human Genetics (ASHG) 2014 Annual Meeting in San Diego.

Rheumatoid arthritis, a painful inflammatory condition that primarily affects the joints, has been tied to a variety of genetic and environmental factors, including lifestyle factors and previous infections. Women are three times more likely to develop rheumatoid arthritis than men, with peak rates among women in their 40s and 50s. Certain versions of the immune system gene HLA-DRB1, known collectively as the shared epitope alleles, are associated with the condition. HLA genes are best known for their involvement in the immune system's response to infection and in transplant medicine for differentiating between one's own cells and those that are foreign.

The female predilection of rheumatoid arthritis strongly suggests that factors involved in pregnancy are involved, said Giovanna Cruz, MS, graduate student at the University of California, Berkeley, and first author on the new study.

"During pregnancy, you'll find a small number of fetal cells circulating around the mother's body, and it seems that in some women, they persist as long as several decades. Women with rheumatoid arthritis are more likely to have this persistence of fetal cells, known as fetal microchimerism, than women without the condition, suggesting that it is a potential risk factor for the development of rheumatoid arthritis," Ms. Cruz said. "Why it happens, we don't know, but we suspect HLA genes and their activity may be involved," she explained.

The researchers analyzed the genes of women with and without the shared epitope or other forms of HLA genes associated with risk of rheumatoid arthritis, and their children. They found that having children with these high-risk alleles inherited from the children's father increased the women's risk of rheumatoid arthritis, even after accounting for differences among the mothers' genes. These results showed that beyond a woman's own genetic risk of rheumatoid arthritis, there is additional risk conferred by carrying and bearing children with certain high-risk alleles.

"We don't yet understand how the shared epitope and other HLA alleles influence rheumatoid arthritis risk, but one possibility is that interactions between the proteins these genes encode may stimulate the autoimmune symptoms of the disease," Ms. Cruz said. In other words, a woman's immune system may detect proteins produced by the fetus and mistakenly tag lingering fetal cells as a threat, causing an immune reaction and symptoms of rheumatoid arthritis.

In addition to explaining why women are at increased risk of rheumatoid arthritis, the findings may lead to new ways of assessing a woman's risk of disease depending on whether her children or partner carries high-risk versions of genes, an area of research that Ms. Cruz and her colleagues are planning to explore. Other future research includes genetically analyzing multiple generations of rheumatoid arthritis cases, including mothers of people with the disease, and further exploring the role of HLA-encoded proteins and microchimerism.

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Children's genes affect their mothers' risk of rheumatoid arthritis